Global spread of malaria and resurgence of drug resistant parasites in various regions of the world has created an urgent need for novel chemotherapies. The goal of malaria chemotherapy in general, and of this proposal in particular, is two fold: to selectively affect infected cells with minimal damage to the host organism and to eliminate parasites, including those of highest drug resistance nature. The means by which this goal is meant to be accomplished comprises synthesis and evaluation of novel agents as well as assessment of their mode of action. Two concepts developed in the participating laboratories provide the basis of the proposal: a. selective targeting of drugs based on differential permeation (the ostensible differences in permeation properties of P. falciparum infected red blood cells previously characterized in biophysical terms, serve here as the main route for drug access into infected cells and b. drug design based on a biomimetic approach of iron(III) chelation and modular building for optimizing drug properties (biochemical and pharmacological). The novel drugs are iron carriers based on both ferrichrome and ferrioxamine which are synthesized with requisite hydrophobicity and/or dimensions so as to exert differential deprivation of intracellular iron (III) pools. Novel agents tested for their ability (dose and speed of action) to arrest in vivo parasite growth including drug resistant P. falciparum strains and to arrest in vivo growth in model rodent animals,provided ample support for the feasibility of all the proposed approaches. The additional rationale on which the work lies, is that unlike cells of the mammalian organism which can demonstrably withstand temporary iron deprivation (chelator treatment) regimes and can fully recover from them, intracellular parasites apparently can not. Support for that hypothesis encompasses: modular drug design of traceable (fluorescent and radioactive) forms of chelators with variable size and hydrophobicities and their application for time-resolved tracing of drug permeation into parasitized cells (at various developmental stages), for compartmental drug distribution, for identification of putative biochemical targets (activities associated with iron containing enzymes and parasite-derived endogenous iron(III) shuttles/ carriers) and for assessment of iron acquisition paths in parasitized cells. The project is meant to provide both scientific and applicative grounds for alternative or supplemental chemotherapy for a disease whose eradication is still considered a major health target for mankind.